Purpose The purpose of this study is to examine the effects of fatigue on muscular performance, oxygenation saturation, and cognition following acute hypoxic exposure at Normoxia, Moderate Hypoxia (MH), and Severe Hypoxia (SH). Methods Twelve males performed 3 sets of leg extensions to failure under Normoxia (FiO2: 21%), MH (Fi02: 15.4%), and SH (Fi02: 12.9%). Heart rate, peripheral oxygenation saturation, total saturation index, psychomotor vigilance testing reaction time, psychomotor vigilance error rate, maximum strength, and repetitions to failure were measured throughout each visit. Results The primary findings indicated that MH and SH resulted in significant decreases in psychomotor vigilance test performance (MH: 388.25–427.17 ms, 0.41–0.33 error rate; SH: 398.17–445.42 ms reaction time, 0.25–1.00 error rate), absolute muscle tissue oxygen saturation (Abs-StO2) (MH:67.22% compared to SH:57.56%), but similar muscular strength, heart rate, and patterns of muscle tissue oxygen saturation responses (StO2%) during fatigue when compared to Normoxia. There was an acute decrease in the ability to remain vigilant and/or respond correctly to visual stimuli as indicated by the worsened reaction time (PVTRT) during MH (FiO2: 15.4%) and increased PVTRT and error rate (PVTE) during SH (FiO2: 12.9%) conditions. Conclusions Acute hypoxic exposure in the current study was not a sufficient stimuli to elicit hypoxic-related changes in HR, muscular strength (1-RM), or repetitions to failure. The SpO2 responses were hypoxic-level dependent with increasing levels of hypoxia resulting in greater and more sustained reductions in SpO2. The combined SpO2 and StO2 responses at MH and SH suggested a balance between the muscles metabolic demand remaining lower than the muscle oxygen diffusion capacity. During the SH condition, Abs-StO2 suggested greater metabolic stress than Normoxia and MH conditions during the fatiguing leg extensions. The patterns of responses for StO2% during the three sets of leg press to failure indicated that exercise is a more potent influencer to muscle oxygenation status than hypoxic conditions (FiO2: 15.4 and 12.9%).